Clinical Significance of the Duality of Wnt/β-Catenin Signaling in Human Hepatocellular Carcinoma

SIMPLE SUMMARY: Wnt/β-catenin mutations in HCCs have a dual phenotype. Jekyll phenotype is defined by high HNF4α status which represses EMT, found in well-to-moderately differentiated HCCs with low AFP levels and good prognosis. HNF4α induces the expression of OATP1B3, which can be recognized as higher enhancement nodules in the hepatobiliary-phase of Gd-EOB-DTPA-enhanced MRI. On the other hand, Hyde phenotype is defined by high FOXM1 status which promotes EMT, found in poorly differentiated HCCs with high AFP levels, positive stem cell markers and poor prognosis. FOXM1 induces the expression of GLUT1, which can be recognized with FGD-PET/CT. HCC with activated Wnt/β-catenin signaling pathway. It could be hypothesized that the former should be mainly resistant to immune checkpoint inhibitors, while the latter would be immune activated and exhausted. In the future, the activation of the Wnt/β-catenin signaling pathway should be detected non-invasively and applied to the treatment of advanced HCC. ABSTRACT: Combination therapy with immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor inhibitors has been approved as a first-line treatment for unresectable hepatocellular carcinoma (HCC), indicating a critical role of ICIs in the treatment of HCC. However, 20% of patients do not respond effectively to ICIs; mutations in the activation of the Wnt/β-catenin pathway are known to contribute to primary resistance to ICIs. From this point of view, non-invasive detection of Wnt/β-catenin activation should be informative for the management of advanced HCC. Wnt/β-catenin mutations in HCC have a dual aspect, which results in two distinct tumor phenotypes. HCC with minimal vascular invasion, metastasis, and good prognosis is named the “Jekyll phenotype”, while the poorly differentiated HCC subset with frequent vascular invasion and metastasis, cancer stem cell features, and high serum Alpha fetoprotein levels, is named the “Hyde phenotype”. To differentiate these two HCC phenotypes, a combination of the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced magnetic resonance imaging and fluoro-2-deoxy-D-glucose-PET/CT may be useful. The former is applicable for the detection of the Jekyll phenotype, as nodules present higher enhancement on the hepatobiliary phase, while the latter is likely to be informative for the detection of the Hyde phenotype by showing an increased glucose uptake.